Correlating HSV-2 Disease Severity with Tissue Resident CD8 T-cells

将 HSV-2 疾病严重程度与组织驻留 CD8 T 细胞相关联

基本信息

批准号：
8565777
负责人：
Jia Zhu
金额：
$ 27.66万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8565777
关键词：
Affect Anatomic Sites Anatomy Animal Model Antigenic Specificity Antigens Antiviral Agents Biopsy Blood Blood Vessels CD4 Positive T Lymphocytes CD8B1 gene Cell Survival Cells Characteristics Clinical Clinical Research Collaborations Confocal Microscopy Containment Dermal Dermis Disease Disease Outcome Exhibits Frequencies Funding Genes Genital system Genome Grant Herpesvirus 1 Human Human Herpesvirus 2 Human Volunteers Immune Immune response Immunity Immunologic Surveillance In Situ Individual Infection Instruction Kinetics Knowledge Laboratories Lesion Lytic Measures Memory Messenger RNA Metabolic Metabolism Methods Mucosal Immunity Mucous Membrane Mus Outcome Participant Pathogenesis Patients Peripheral Physiological Play Population Positioning Attribute Property Proteins Recurrence Role Sampling Sensory Nerve Endings Severity of illness Simplexvirus Site Skin Study models T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Tissues Ulcer Vaccine Design Vaccines Vaccinia virus Viral Virion Virus Virus Diseases cell type chemokine clinical epidemiology cohort cytokine deep sequencing density genital herpes human data human tissue in vivo insight laser capture microdissection particle pathogen reactivation from latency response spatiotemporal vaccine development

项目摘要

Herpes simplex virus type-2 (HSV-2) infections are lifelong, and a leading cause of genital ulcer disease woridwide. The clinical outcome of genital HSV-2 reactivation varies widely from completely asymptomatic to infrequent and short-lasting recurrences to frequent and severe genital ulcerations: reasons forthis variability are not known. Using biopsies of genital skin and mucosa from human volunteers, we have shown that HSV-2 reactivation results in a long-term persistence of local immune responses. CDS T cells persist at the dermal-epidermal junction (DEJ) contiguous to the sensory nerve endings where virions are released. The unique anatomical distribution suggests that local CDS T cells might play a pivotal role in rapid containment of viral infection in the periphery, thus inflijencing the clinical and virologic course of HSV-2 disease in humans. In the last grant cycle, we developed a cell-type specific laser capture microdissection (LCM) method to isolate individual CDS T cells in situ and measure their activity. By using combined approaches of CDS-specific LCM, whole genome transcriptional profiling and TCR repertoire deep sequencing, we can now elucidate associations between tissue resident memory CDS T cells and genital herpes disease severity in humans. In this project, we will investigate the association between HSV-2 disease severity and the quantity, quality and diversity of tissue resident memory CDS T cells at the site of previous HSV-2 recurrence in humans. Our specific aims are: 1) to define whether the anatomic distribution, density, decay kinetics and the antiviral signature genes of tissue resident memory CDS T cells differ in participants with mild versus severe genital HSV-2 diseases; 2) to define whether the T cell receptor (TCR) repertoire dynamics and antigenic specificity of tissue resident memory CDS T cells are associated with genital herpes disease severity. We will obtain sequential biopsy tissues from patient cohorts with distinct disease outcomes: mild disease, defined as recurrence rate < 2 episodes per year and severe disease as recurrence rate > 6 episodes per year. This project will define the characteristics of a successful peripheral immune response to HSV-2 that can be harnessed as a potential correlate of immunity during vaccine development. RELEVANCE (See instructions): Genital herpes affects 17% of US population; no cure or vaccine is available. We do not know why some people with this infection have severe disease, and others very mild. We have developed new laboratory methods to study immune cells in samples from people with genital herpes that we will apply to understand the difference between people with mild and severe disease in order to develop an effective vaccine.

2 型单纯疱疹病毒 (HSV-2) 感染是终生的，并且是生殖器溃疡病的主要原因全球范围内。生殖器 HSV-2 重新激活的临床结果差异很大，从完全无症状到罕见且短暂的复发到频繁且严重的生殖器溃疡：这种变异性的原因不知道。通过对人类志愿者的生殖器皮肤和粘膜进行活检，我们发现： HSV-2 重新激活导致局部免疫反应长期持续。 CDS T 细胞持续存在于真皮表皮连接处 (DEJ) 邻近释放病毒颗粒的感觉神经末梢。这独特的解剖分布表明局部 CDS T 细胞可能在快速遏制中发挥关键作用外周病毒感染，从而影响 HSV-2 疾病的临床和病毒学过程人类。在上一个资助周期中，我们开发了一种细胞类型特异性激光捕获显微切割（LCM）原位分离单个 CDS T 细胞并测量其活性的方法。通过使用组合方法 CDS 特异性 LCM、全基因组转录谱和 TCR 库深度测序，我们现在可以阐明组织驻留记忆 CDS T 细胞与生殖器疱疹疾病严重程度之间的关联人类。在这个项目中，我们将研究 HSV-2 疾病严重程度与数量之间的关联，先前 HSV-2 复发部位的组织驻留记忆 CDS T 细胞的质量和多样性人类。我们的具体目标是：1）定义解剖分布、密度、衰变动力学和组织驻留记忆 CDS T 细胞的抗病毒特征基因在轻度和中度患者中存在差异严重的生殖器 HSV-2 疾病； 2) 确定 T 细胞受体 (TCR) 的动态特性和组织驻留记忆 CDS T 细胞的抗原特异性与生殖器疱疹疾病相关严重程度。我们将从具有不同疾病结果的患者队列中获得连续活检组织：轻度疾病，定义为复发率<每年2次，严重疾病定义为复发率>6 每年剧集数。该项目将定义成功的外周免疫反应的特征 HSV-2 在疫苗开发过程中可被用作免疫的潜在相关因素。相关性（参见说明）：生殖器疱疹影响着 17% 的美国人口；没有可用的治疗方法或疫苗。我们不知道为什么有些感染这种病毒的人病情较重，而其他人则病情较轻。我们开发了新的实验室研究生殖器疱疹患者样本中免疫细胞的方法，我们将应用这些方法来了解区分轻度和重度疾病的人，以便开发有效的疫苗。